Ruminant deglutition alteration

ABSTRACT

A method and composition useful for altering deglutition in ruminants by closure of the esophageal groove therein are disclosed. In the method and composition, guanidine, 1aminoguanidine, 1,3-diaminoguanidine or a pharmaceuticallyacceptable salt thereof are employed to close the esophageal groove of a ruminant animal, thereby permitting orally-ingested nutrients and medicaments to bypass the reticulo-rumen.

[451 Aug. 1, 1972 Elite States atent Johnston et al.

[54] RUMINANT DEGLUTITION ALTERATION [72] Inventors: Charles Johnston;Michael D.

Campbell, both of Midland, Mich.

[73] Assignee: The Dow Chemical Company,

Midland, Mich.

[22] Filed: Dec. 26, 1968 [21] Appl. No.: 787,220

[52] U.S. Cl ..424/326 [51] Int. Cl. ..A6lk 27/00 [58] Field of Search..424/326 [56] References Cited OTHER PUBLICATIONS Ueda-Chem. Abst. Vol.59 (1963) page 141 12a Armstrong-Chem. Abst. Vol. 51 (1957) page 2552bKing-Chem. Abst. Vol. 57 (1962) pages l5564h & 15565 Taylor-Chem. Abst.Vol. 55 (1961) pages 27377i & 27378 Primary Examiner-Sam RosenAttorney-Griswold & Burdick, Maynard R. Johnson and John L. Spalding [57] ABSTRACT A method and composition useful for altering deglutition inruminants by closure of the esophageal groove therein are disclosed. Inthe method and composition, guanidine, l-aminoguanidine,1,3-diaminoguanidine or a pharmaceutically-acceptable salt thereof areemployed to close the esophageal groove of a ruminant animal, therebypermitting orally-ingested nutrients and medicaments to bypass thereticulo-rumen.

14 Claims, N0 Drawings RUMINANT DEGLUTITION ALTERATION BACKGROUND OF THEINVENTION The Ruminantia, that is, the ruminants, such as sheep, cattleand goats, have the ability to consume and utilize cellulosic feedstuffswhich are of negligible value to monogastric animals such as dogs, cats,monkeys and the like. This is possible because of the pre-gastricfermentation processes occuring in reticuloreumen compartments of theruminant animals stomach. Such pre-gastric fermentation processesconvert these feedstuffs into nutrients which can, upon subsequentpassage to other parts of the digestive system, be utilized by theanimal. Unfortunately, feedstuffs which could be better utilized withoutpre-gastric fermentation also enter the same processes in the ruminantanimal as do feedstuffs of negligible value, resulting in the loss ofnutrients.

In the ruminant animal, ingested food passes from the esophagus to thereticulo-rumen for pre-gastric fermentation, then to the omasum andabomasum before entering the small intestine. The stomach of theruminant is divided into four compartments; reticulum, rumen, omasum andabomasum. The reticulum and rumen are joined by a fold of tissue, sothat ingesta flows freely from one to the other. Most of the microbialactivity of pre-gastric fermentation takes place in the reticulo-rumen.The function of the abomasum appears to be similar to the simple stomachof the monogastric species. The function of the omasum has not beenclearly defined.

In young suckling ruminant animals the esophageal groove, a continuationof the esophagus as a groove or tube which bypasses the reticulo-rumenarea, functions to bypass milk from the esophagus to the reticuloomasalorifice where it enters the omasal-abomasal compartments. As theruminant animal becomes older and changes from a liquid to a solid diet,the reticulorumen develops and pre-gastric fermentation begins. Theesophageal groove mechanism of bypassing the reticulo-rumen area thendiminishes and deglutition alters so that all ingested materials passfirst into the reticulo-rumen area rather than the omasal-abomasalcompartments.

Not only do cellulosic feedstuffs enter reticulorumen area and undergopre-gastric. fermentative processes, but medicaments and nutrients suchas simple sugars, essential amino acids, peptides and proteins alsoundergo the same processes resulting in a partial or complete loss oftheir activity. For example, anthelrnintic medicaments such astetrachloroethylene and nicotine sulfate are so degraded in thereticulo-rumen as to be of little use in treating ruminant animals.Supplemental nutrients such as glucose, fat soluble vitamins, lysine,methionine, cysteine, cystine and other protein, peptide and amino acidnutrients are so degraded by the microflora of the pre-gastricfermentation processes in the recticulo-rumen that they are of little orno value as dietary supplements for ruminants. Riek, Australian Vet.Jour. 30: 29 (1954); McDonald, Biochem. J., 42: 584 (1948); Marston,Aust. J. Exp. Biol. Med. Sci. 9: 235 (1932); Dutoit et al., J. Vet.Sci., 4: 229 (1935); Reis et al., Australian J. Agr. Res. 12: 335(1961); Australian J. Biol. Sci. 16: 218 (1963); and Australian J. Biol.Sci. 1 7: 532 (1964); and Reis, Australian J. Biol. Sci. 20: 809(bl967).

Various procedures for stimulating the growth of reticulo-rumenmicroflora are known. Amidines, including guanidine, are known to beuseful as sources of usable nitrogen for the rumen microflora ofRuminantia, and have been shown to enhance the growth of such microflorain vitro, US. Pat. No. 2,630,386.

There is a need for a simple method and composition which will alter thedeglutition process in ruminants so that orally ingested materialssusceptible to degradation by rumen microflora are protected therefromand shunted to the omasal-abomasal compartments.

SUMMARY OF THE INVENTION The present invention is directed to themodification of the deglutition processes in ruminant animals wherebyorally ingested materials are shunted to the omasal-abomasalcompartments of the ruminant animal stomach, substantially bypassing thereticulorumen compartments. More particularly, the invention is directedto a process in which the esophageal tissues of a ruminant animal aresubjected to the action of one or more compounds selected fromguanidine, l-aminoguanidine, 1,3-diarninoguanidine and thepharmaceutically acceptable salts thereof in an amount sufficientsubstantially to close the esophageal groove of the animal. Such closureof the esophageal groove substantially prevents entry of swallowed ororally ingested material into the reticulo-rumen, thus bypassing thereticulo-rumen and shunting such material to the omasal-abomasalcompartments for utilization by the ruminant animal. The invention thusincludes a procedure useful for the oral administration to animals ofeffective amounts of rumen-degradable or rumen-insensitive, gastricallyutilizable materials, the procedure comprising exposing the esophagealtissues of a ruminant animal to sufficient of one of the activecompounds of the invention to substantially close the esophageal groovethereof, and orally administering to the animal a rumen-degradable orrumen-insensitive, gastrically utilizable substance while the esophagealgroove is substantially closed.

The guanidine, l-aminoguanidine and 1,3- diaminoguanidine activecompounds employed in the method of the invention are well knowncompounds which have no substantial adverse effects on ruminant animalswhen employed at dosages consistent with good esophageal groove-closingactivity. The term esophageal tissues, as employed in the presentspecification and claims, means and refers to the tissues of theesophagus and of the oral cavity at or near the esophagus, and isinclusive of those tissues of the esophagus and of the rear portions ofthe oral cavity which are contacted by material which is swallowed orabout to be swallowed during the normal processes of deglutition. Theesophageal tissues of the ruminant animal can be exposed to the actionof the active com pounds by a suitable procedure such as oraladministration in the form of solid or liquid compositions, by mixingthe active compounds with dry or liquid animal feed, or feedsupplements, or by liquid drenching procedures. The active compounds arepreferably employed in the form of a pharmaceutically acceptable saltthereof, and pharmaceutically acceptable salts of guanidine orl-aminoguanidine are particularly preferred.

As employed herein, the phrase pharmaceutically acceptable salts refersto non-toxic salts of the active compounds, the anions of which arerelatively innocuous to the ruminant animal at dosages consistent withgood esophageal groove-closing activity so that the beneficial effectsof the compounds are not vitiated by side effects ascribable to theanions. Appropriate pharmaceutically acceptable salts include thosederived from mineral acids such as hydrochloric, hydrobromic, carbonic,phosphoric, sulfuric, chromic and nitric'acicls and from organic acidssuch as acetic, lactic, maleic, succinic, fumaric, glutaric, citric,malic and tartaric acids and the like. The hydrochloride salts arepreferred.

The term rumen-degradable, gastrically utilizable substance," asemployed in the present specification and claims, means and refers tothose substances such as medicaments, including antiparasitic agents andpharmacologically active agents, and nutrients, including simple sugarsand essential amino acid sources, which are of substantial benefit tothe ruminant animal either nutritionally or in treatment of infection orthe like if administered through the omasal-abomasal compartments, butwhich are substantially reduced in efficacy by passage through thereticulo-rumen when administered orally. Representativerumen-degradable, gastrically utilizable substances include medicamentssuch as tetrachloroethylene, nicotine sulfate, and bacitracins; andnutrients, such as sugars, including glucose, fructose, sucrose,maltose, lactose and the like; fat soluble vitamins, such as vitamin A,vitamin D, vitamin E and vitamin K; and sources of essential aminoacids. The term essential amino acid source, as employed herein, refersto materials which supply amino acids essential in ruminant metabolism,and including the amino acids themselves such as lysine, methionine,cystine, cysteine, tryptophan, arginine, threonine, or glycine as wellas digestible peptides, polypeptides, and proteins containing the same.

The rumen-insensitive, rumeninsensitive, gastrically utilizablesubstance, as employed in the present specification and claims, meansand refers to those substances which are absorbed into the animal systemfrom the omasal-abomasal compartments rather than from term thereticulo-rumen. Such substances are of substantial benefit to theruminant animal either nutritionally or in treatment of infection or thelike if administered through the omasal-abomasal compartments, but arenot absorbed in substantial amounts directly from the reticulo-rumen.Consequently, the beneficial properties of such substances are notordinarily utilizable by ruminant animals immediately following oraladministration thereof, utilization by the animal being delayed by asmuch as 72 to 96 hours while the substance passes through thereticulo-rumen. Certain rumen-insensitive, gastrically utilizablesubstances, notably antibiotics such as the tetracyclines includingtetracycline, chlortetracycline and oxytetracycline, chloramphenicol,erythromycin, penicillins, and tylosin, are not only delayed in actionby passage through the reticulo-rumen, but have a temporary detrimentaleffect on ruminant digestion due to their suppression of rumenmicroflora.

The method and composition of the invention are of particular value inthe oral administration of rumendegradable, gastrically utilizablesubstances to ruminants, since the invention permits the animal to makephysiological use of substances which otherwise would be rendered oflittle value to the animal. The invention can also be employed toadvantage in the oral administration of substances which can be utilizedby the animal when received in the omasal-abomasal compartmentsregardless of whether the substance passes through the reticulo-rumen ornot. In this event, rumen-insensitive gastrically utilizable substancesarrive in the omasalabomasal compartment substantially sooner afteradministration, thus substantially eliminating the time normally spentin the reticulo-rumen before the substance can be utilized by theanimals. It is essential, however, that the method of the invention notbe practiced while the animal is being orally administered substantialamounts of substances which are not utilizable by the animal withoutpre-gastric fermentation in the reticulo-rumen. Since the practice ofthe present method results in closure of the esophageal groove andshunting of substantial amounts of orally consumed materials directly tothe omasum-abomasum and bypassing the reticulo-rumen, substancesnormally requiring pre-gastric fermentation can be reduced ineffectiveness. Consequently, the materials utilized by pre-gastricfermentation, such as cellulosic feedstuffs, hay, grass and the like,should be fed a sufficient time after the treatment with the guanidineand laminoguanidine compounds for the esophageal groove to re-open andfor substantially normal deglutition to be resumed.

Whether or not a particular substance is a rumendegradable,gastrically-utilizable substance or a rumeninsensitive,gastncally-utilizable substance suitable for use in the method of theinvention can be readily determined by known. procedures. For example,routine comparisons can be carried out between oral administration viaconventional and normal deglutition, involving passage through thereticulo-rumen, and administration directly into the omasum-abomasum bythe method of the invention or by cannulation, administration throughfistulae or the like.

The exposure of the esophageal tissues of a ruminant to the action of anamount of guanidine, laminoguanidine, 1,3-diaminoguanidine or apharmaceutically acceptable salt thereof sufficient to bring aboutsubstantial closure of the esophageal groove is critical and essentialto the practice of the present invention. Expressions such as sufficientto close substantially the esophageal groove andesophagealgroove-closing amount are employed in the presentspecification and claims to designate that amount of active compoundwhich is sufficient to induce substantial closure of the esophagealgroove as indicated by the shunting to the omasum-abomasum or bypassingof the reticulo-rumen of substantial amounts of substances ingestedsimultaneously with, or within a short time after, the administration ofthe guanidine or aminoguanidine compound. Whether or not sufficient ofan active compound is employed and whether or not the particularprocedure employed exposes the esophageal tissues to sufficient activecompound under particular circumstances can be ascertained byconventional testing procedures such as administration of glucose andanalysis of blood sugar levels, or administration or a dye such as Congored followed by necropsy to determine the location of the major amountof the dye.

The amount of active compound to be administered to a ruminant animalcan vary depending upon such factors as the particular compound or saltemployed, the size, weight, age and species of ruminant animal treated,the time of administration, whether or not the compound is administeredin a solid feed supplement composition or in a liquid composition suchas in liquid diet supplements in drinking water or as a drench, and theparticular effects desired to be produced, that is, whether it isdesired only to provide a desired closure of the esophageal groove for ashort period of time such as in oral administration of medicaments, orwhether substantially continuous bypassing of the reticulorumen isdesired for longer periods, as in the feeding of low-cellulose, highsugar, high protein and amino acid diets and supplements.

In general, the compounds are administered in liquid solution ordispersion or in a solid form adapted to be readily dispersed ordissolved in the oral secretions of the ruminant prior to deglutition.Oral administration of the compounds in such compositions provides forspreading and dispersal of the dose of compound over the esophagealtissues of the animal as the composition moves from the oral cavity andinto the esophagus during deglutition or drenching. In contrast, oraladministration of the active compounds in compacted or nondispersibleform, such as the oral administration of the compounds in tablets,boluses, gelatin capsules, pills or the like, which are swallowed whole,prevents the exposure of the esophageal tissues to the action of thecompounds and results in no alteration from the normal deglutitionprocess. In such cases, the non-dispersible composition is carried tothe reticulo-rumen. Excellent results in alteration of ruminantdeglutition are obtained when the active compounds are administered inthe form of orally ingestable compositions containing from about 0.005to about one to about two percent by weight of guanidine,l-aminoguanidine, 1,3- diaminoguanidine or a pharmaceutically acceptablesalt thereof. Such compositions can be administered in amountssufficient to provide from about 0.5 or less to about 1,000 or moremilligrams of compound per pound of animal body weight, with excellentresults being obtained when the compounds are administered at oraldosage rates of from about 0.5 to about 10, to about 25 milligrams perpound. Oral administration of such amounts of the compounds, either infinely divided dispersible solid form or in liquid solution providessubstantial closure of the esophageal groove persisting for about 2 to 5minutes following a single dose. Oral administration of gastricallyutilizable substances, either simultaneously with the guanidine r monoordiaminoguanidine compound or within about 2 to about 5 minutes afteradministration of an active compound results in shunting of suchsubstances to the omasum-abomasum and bypassing of the reticulo-rumen.

The method of the invention is preferably carried out by the oraladministration to a ruminant animal of a composition comprising anesophagealgroove-closing amount of one or more of guanidine,laminoguanidine, 1,3-diaminoguanidine and the pharmaceuticallyacceptable salts thereof in intimate admixture with one or morerumen-degradable, gastrically utilizable substance or rumen-insensitive,gastrically utilizable substance. Such compositions preferably containonly minor amounts, such as less than about 15 percent by weight ofcellulosic materials or other substances utilized only by pre-gastricfermentation. Preferably, the compositions contain a disperse ordispersible form of the active compound, that is, the compositions areeither liquids in which the active compounds are dispersed or dissolved,or finely divided solids in which the compounds are dispersed. In apreferred embodiment, the solid compositions are sufficiently finelydivided so that more than 50 percent thereof passes a screen having 4meshes to the inch and more than percent of the active compound thereinis sufficiently finely divided to pass a similar screen.

Solid compositions typically contain rumen-degradable, gastricallyutilizable nutrient substances such as dextrose, sucrose, lactose,maltose, corn syrup solids, hydrolyzed cereal solids, dry milk solids,cracked or milled grains such as corn, wheat, oats, barley, and thelike, dried molasses, dried sorghum, soybean meal, cottonseed meal,peanut meal, fish meal, lysine, methionine, cystine, cysteine,tryptophan, arginine, glycine, peptides and polypeptides containinglysine, cysteine, cystine, tryptophan, arginine, glycine, methionine andthe like, casein, soya bean protein and the like; fat soluble vitamins,such as vitamin A, vitamin D, vitamin E or vitamin K; as well asrumen-insensitive, gastrically utilizable mineral nutrients such asferrous salts, sodium chloride, magnesium sulfate, calcium salts,buffers and the like, and from about 0.005 to about 1 to about 2 percentby weight of one or more of the active guanidine or aminoguanidinecompounds. Desirable solid compositions contain from about 0.05 to about98 percent by weight of an essential amino acid source in the form ofamino acids or salts'thereof, peptides, polypeptides or proteins.Preferred protein supplement compositions contain from about 35 to about40 to about 75 percent by weight of essential amino acid source and fromabout 0.05 to about 0.5 percent by weight of an active compound.Concentrate supplement compositions generally contain from about 0.5 toabout 2 or more percent of an active compound, and may also contain fromabout 50 to about 98 percent of an essential amino acid source. Theconcentrate supplement concentrations are adapted to be diluted withother nutrients such as sugars or cereals prior to feeding. Thesupplement compositions are typically fed orally in amounts of about 1to about 6 to about 10 grams of composition per pound of animal bodyweight per day, and are preferably so formulated so that en entire dailydosage of the desired supplemental nutrients is incorporated with asingle dosage of from about 0.5 to about 1,000 milligrams of activecompound per pound of animal body weight.

Liquid compositions typically comprise one or more of the gastricallyutilizable substances set out above, and in addition thereto theycomprise a liquid carrier such as water, milk, aqueous ethanol,propylene glycol, glycerine, polyethylene glycols and the like.Emulsified compositions can contain edible oils such as corn oil, peanutoil, cottonseed oil and the like, as well as surface active dispersingagents or emulsifying agents. The liquid compositions contain anesophageal-grooveclosing amount of from about 0.005 to about 1 to about2 percent by weight of one or more of the guanidine, laminoguanidine or1,3-diaminoguanidine active compounds.

The solid and liquid compositions of the invention can also containrumen-degradable, gastrically utilizable or rumen-insensitive,gastrically utilizable medicaments in addition to or in lieu of thenutrient substances described above. Preferred rumen-degradable,gastrically utilizable medicaments include tetrachloroethylene, nicotinesulfate and bacitracins such as bacitracin, zinc bacitracin, manganesebacitracin or bacitracin methylenedisalicylate. Preferredrumen-insensitive, gastrically utilizable medicaments includechloramphenicol, tylosin, erythromycin, penicillins and tetracyclines,such as tetracycline, oxytetracycline or chlorotetracycline.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examplesillustrate the invention but are not to be construed as limiting thesame.

EXAMPLE 1 Several groups of docile crossbred lambs of both sexes andweighing between 60 and 70 pounds each are administered anesophageal-groove-closing amount of one of the active compounds of theinvention in a procedure similar to that described by Rick, AustralianVet. Jour. 30: 29-37 (1954). The lambs are penned in groups of six lambsper group and fed a conventional hay-grain ration. Feed is withheld fromthe animals for 16 hours before administration of a test compound. Bloodsamples are taken from the jugular vein and transferred to heparinizedcentrifuge tubes prior to treatment. The blood samples are analyzed forglucose content. Each group of lambs is drenched with 30 milliliters ofan aqueous composition containing a test compound and drenchedthereafter with 60 milliliters of an aqueous solution containing 83.3percent by weight of glucose. Drenching with glucose is carried outwithin seconds of drenching with a test compound. Drenching with bothtest compound and with the glucose solution is carried out using asyringe type drenching gun with a flexible plastic extension tube toensure contact of the test compound solutions with esophageal tissues. Asimilar group of similar lambs is similarly prepared as a check. Thecheck lambs are drenched with 30 milliliters of water prior to drenchingwith glucose solution, and these animals are not treated with a testcompound. A second blood sample is drawn from the jugular vein of eachanimal 1 hour after drenching with glucose, and the blood glucoseconcentration is determined and compared to the concentration observedprior to drenching. An average increase in blood glucose level ofgreater than 10 milligrams of glucose per 100 milliliters of blood isobserved with each group of lambs treated with a test compound,indicating closure of the esophageal groove. The results of theseobservations are set out below in Table l, showing the average bloodglucose levels observed prior to treatment and one hour after treatment,and the average increase in glucose level obtained with each testcompound.

TABLE I Amt. Administered in mg. Av. blood glucose level per 60-70 lb.Before After he- Test Compound Lamb treatment treatment rease mg. per100 milliliters None (check group) 62.4 64.1 !.7 l -Aminoguanidine 77 7l .0 90.6 l 9.6 bicarbonate l,3-Diaminoguan- 600 70.8 93.2 22.4 idinehydrochloride l-Aminoguanidine 55 61.2 81.9 20.7 hydrochloride Guanidinechro- 600 67.7 97.2 29.6 mate Guanidine phos- 600 65.9 91.0 25.1 phateGuanidine hydro- 55 78.1 105.7 27.6 chloride EXAMPLE 2 Separate groupsof 60 to pound lambs are prepared as described above in Example l. Feedis withheld from the animals for approximately 16 hours (overnight)before feeding a test ration. Blood samples are taken from the jugularvein of each animal, transferred to heparinized centrifuge tubes priorto treatment and analyzed for blood glucose level. The sheep are thenfed a dry feed test ration consisting of 35 percent by weight glucosemonohydrate in a conventional feed supplement containing equal parts ofcorn and oats. The test rations are intimately mixed with anesophageal-groove-closing amount of a test compound prior to feeding.One-half pound of test ration is fed to each sheep. A similar checkgroup of sheep is similarly fed an identical test ration which containsno test compound. Blood samples are taken 1.5 hours after feeding andanalyzed for blood glucose concentration. The results obtained with eachgroup are set out below in Table II.

TABLE II Av. glucose level Separate groups of sheep are administered atest compound and a Congo red dye indicator in drenching and feedingoperations similar to those of Examples 1 and 2. A first series ofseparate groups of sheep are drenched with 30 milliliters of an aqueoussolution containing 600 milligrams of one of guanidine phosphate orguanidine chromate or containing 55 milligrams of guanidinehydrochloride. A drenching check group is administered 30 milliliters ofwater. Each group in this series is then drenched within 15 to 30seconds with 60 milliliters of aqueous 83.3 percent glucose solutioncontaining one percent by weight of Congo red dye. A second series ofsheep is fed the test ration of Example 2 containing 35 percent glucoseand l percent Congo red dye. One such group receives one-half pound persheep of such feed composition having 0.083 percent by weight ofguanidine hydrochloride incorporated therein. A second such groupreceives an identical ration containing 0.167 percent guanidinehydrochloride, and a feeding check group receives an identical rationcontaining no test compound. Analyses of blood sugar levels beforedrenching or feeding and l hour after drenching or 1.5 hours afterfeeding indicate substantial increases of blood glucose in the sheepreceiving the guanidine test compounds and negligible increases in thecheck groups of sheep. The animals are then slaughtered and a carefulsearch of the gastro-intestinal tract is carried out in each case todetermine the disposition of the Congo red dye. The Congo red dye isfound in the abomasum of the drenched sheep treated with a guanidinecompound and dispersed between the omasum and abomasum of the sheepreceiving dry feed containing guanidine hydrochloride. In the checksheep which were treated by either drenching or feeding but without theaddition of a guanidine compound, all of the dye is found in thereticulo-rumen. In other operations, similar results are obtained withcattle and with goats.

EXAMPLE 4 Separate groups of crossbred lambs and yearling wethers areprepared as test animals. A by 10 centimeter square is marked on bothmid-sides of each sheep and all of the wool is removed from the squarepatch areas with small animal clippers. All sheep are then fed analfalfa hay diet for a base period of 3 weeks. At the end of the 3-weekbase period, the wool is clipped from the patch areas, cleaned, dryed,and weighed to determine the base level of wool production for eachsheep. Following the 3-week base period, three groups of four sheep pergroup are fed 60 grams of a supplemental diet per sheep per day for 3weeks.

The supplemental diet is a dry mash high in essential amino acids andcontaining 78 percent soybean meal, 7.5 percent corn, 7.5 percent oats,5 percent dried molasses solids and 2 percent DL methionine. One groupof sheep receives the supplemental diet admixed with 0.16 percent byweight of guanidine hydrochloride; a second group receives thesupplement admixed with 0.184 percent by weight of laminoguanidinehydrochloride. A third group of sheep receives the supplemental dietalone, without any test compound. In addition, another group of foursheep receives neither a supplemental diet nor a test compound. Thesheep are maintained for the additional 3- week period and are allowedto feed on the alfalfa hay ration ad libitum. At the end of the second3-week period, the wool from the patch areas is again clipped, cleaned,dried and weighed.

The sheep receiving only the alfalfa hay ration and the sheep receivingthe supplemental diet without any guanidine or l-aminoguanidine testcompound are period in which they were fed only the alfalfa hay ration.

EXAMPLE 5 A feed supplement composition is prepared by mixing together34 parts by weights of fish meal, 25 parts by weight of soybean meal, 5parts by weight of each of cracked corn, barley and oats, 2 parts byweight of lysine, 2 parts by weight of methionine, 1 part by weight ofcysteine, 6 parts by weight of casein, 10 parts by weight of corn syrupsolids, 4.5 parts by weight of cottonseed meal and 0.5 part by weight ofguanidine hydrochloride. The supplement is mixed well and vitamins A andD are added to provide 5,000 International Units of Vitamin A and 400International Units of Vitamin D per pound of feed supplement. Thesupplement is adapted to be fed to cattle, feeding of the supplementbeing regulated so that the animals are permitted to feed thereon for alimited time daily, the feeding time being selected to provide foringestion of about 1 gram of composition per pound of body weight.

EXAMPLE 6 A medicated composition is prepared by mixing together 60parts by weight of soybean meal, 30 parts by weight of a mixture ofequal parts of wheat, barley and oats, 5 parts of dried sorghum solids,3 parts of casein, 0.75 part of lysine, 0.70 part of methionine, 055part by weight of l-aminoguanidine carbonate and 0.5 part by weight ofoxytetracycline hydrochloride. The composition is administered orally tocattle and sheep by feeding at a dosage rate of 1 gram of compositionper pound of animal body weight.

EXAMPLE 7 Yearling steers weighing about 500 to 600 pounds each aredosed with nicotine sulfate to combat hookworms. The cattle areadministered 60 milliliters of an aqueous drench containing 150milligrams of guanidine sulfate. Fifteen to 30 seconds thereafter, theanimals are drenched with 120 milliliters of an aqueous solutioncontaining 2.5 percent by weight of nicotine sulfate.

EXAMPLE 8 Two parts by weight of cysteine, 1 part by weight oftryptophan, 2 parts by weight of methionine and one part by weight oflysine are mixed together and milled with 19 parts by weight of barley,5 parts by weight of dried molasses, 10 parts by weight of dried yeast,10 parts by weight of oats, 49 parts by weight of soybean grits, 0.5part by weight of 1,3-diaminoguanidine hydrochloride and 0.5 part byweight of guanidine phosphate to prepare a feed supplement. Thesupplement is adapted to be fed to ruminants in amounts of 50 to gramsper pounds of body weight per day in a single feeding.

What is claimed is:

1. A method which comprises dispersing over the esophageal tissues of aruminant animal by oral administration a compound selected from thegroup consisting of guanidine, l-aminoguanidine, 1,3-diaminoguanidineand the pharmaceutically acceptable salts thereof, in an amountsufficient to induce substantial closure of the esophageal groove of theanimal, and orally administering to the animal while its esophagealgroove is substantially closed, an effective amount of a substanceselected from medicaments and nutrients subject to a substantialreduction in efficacy on passage through the reticulo-rumen, wherebysaid substance is shunted to the omasum-abomasum, substantiallybypassing the reticulo-rumen.

2. The method of claim 1 wherein the compound is selected from the groupconsisting of guanidine and the phannaceutically-acceptable saltsthereof.

3. The method of claim 1 wherein the compound is selected from the groupconsisting of laminoguanidine and the pharmaceutically-acceptable saltsthereof.

4. The method of claim 1 wherein the substance is an essential aminoacid source.

5. The method of claim 1 wherein the substance is an amino acid selectedfrom the group consisting of lysine, methionine, cystine, cysteine,tryptophan, arginine, glycine and threonine.

6. The method of claim 1 wherein a nutrient sub stance is administeredsubstantially simultaneously with the compound.

7. A method which comprises dispersing over the esophageal tissues of aruminant animal by oral administration a compound selected from thegroup consisting of guanidine, l-aminoguanidine, l,3-diaminoguanidineand the pharmaceutically acceptable salts thereof, the compound beingemployed in an amount of from about 0.5 to about 1,000 milligrams ofcompound per pound of animal body weight thereby inducing substantialclosure of the esophageal groove of the animal; and orally administeringto the animal an effective amount of a nutrient or medicament substancewhich is substantially reduced in efficacy by passage through thereticulo-rumen when administered orally, the substance beingadministered during a period from a time simultaneous to administrationof the compound to about 5 minutes thereafter and while the esophagealgroove of the animal is substantially closed, whereby said substance isshunted to the omasum-abomasum, substantially bypassing thereticulo-rumen.

8. The method of claim 7 wherein the substance administered is amedicament selected from the group consisting of tetrachloroethylene,nicotine sulfate, bacitracin, zinc bacitracin, manganese bacitracin andbacitracin methylenedisalicylate.

9. The method of claim 7 wherein the substance administered is amedicament selected from the group consisting of chloramphenicol,tylosin, erythromycin, penicillin, tetracycline, oxytetracycline andchlortetracycline.

10. The method of claim 7 wherein the substance administered is a memberof the group consisting of the amino acids lysine, methionine, cystine,cysteine, tryptophan, arginine, threonine, and glycine and digestiblepeptides, polypeptides, and proteins containing the i fj The method ofclaim 7 wherein the compound is administered by drenching with anaqueous solution containing from about 0.005 to about 2 percent of thecompound, and wherein the substance is orally administered within abouttwo minutes following the administration of the drench.

12. A method which comprises orally administering to a ruminant animal afinely divided solid, ingestible composition comprising from about 0.005to about 2 percent by weight of a compound selected from the groupconsisting of guanidine, l-aminoguanidine, 1,3- diaminoguanidine and thepharmaceutically acceptable salts thereof, and a substance selected fromthe group consisting of dextrose, sucrose, lactose, maltose, corn syrupsolids, hydrolyzed cereal solids, dry milk solids, cracked or milledgrain, dried molasge s, dried sorghum, soybean meal, cottonseed meal,pea'n'ut meal, fish meal, lysine, methionine, cystine, cysteine,tryptophan, arginine, glycine, peptides and polypeptides containinglysine, cysteine, cystine, tryptophan, arginine, glycine, or methionine,casein, soya bean protein, vitamin A, vitamin D, vitamin E, and vitaminK; the composition being administered in an amount sufficient to providefrom about 0.5 to about 1,000 milligrams of said compound per pound ofanimal body weight, whereby said substance is shunted to theomasum-abomasum, substantiaily bypassing the reticulo-rumen.

13. The method of claim 12 wherein the compound is guanidinehydrochloride.

14. The method of claim 12 wherein the composition is administered in anamount sufficient to provide from about 0.5 to about 25 milligrams ofcompound per pound of animal body weight.

2. The method of claim 1 wherein the compound is selected from the groupconsisting of guanidine and the pharmaceutically-acceptable saltsthereof.
 3. The method of claim 1 wherein the compound is selected fromthe group consisting of 1-aminoguanidine and thepharmaceutically-acceptable salts thereof. Pg,26
 4. The method of claim1 wherein the substance is an essential amino acid source.
 5. The methodof claim 1 wherein the substance is an amino acid selected from thegroup consisting of lysine, methionine, cystine, cysteine, tryptophan,arginine, glycine and threonine.
 6. The method of claim 1 wherein anutrient substance is administered substantially simultaneously with thecompound.
 7. A method which comprises dispersing over the esophagealtissues of a ruminant animal by oral administration a compound selectedfrom the group consisting of guanidine, 1-aminoguanidine,1,3-diaminoguanidine and the pharmaceutically acceptable salts thereof,the compound being employed in an amount of from about 0.5 to about1,000 milligrams of compound per pound of animal body weight therebyinducing substantial closure of the esophageal groove of the animal; andorally administering to the animal an effective amount of a nutrient ormedicament substance which is substantially reduced in efficacy bypassage through the reticulo-rumen when administered orally, thesubstance being administered during a period from a time simultaneous toadministration of the compound to about 5 minutes thereafter and whilethe esophageal groove of the animal is substantially closed, wherebysaid substance is shunted to the omasum-abomasum, substantiallybypassing the reticulo-rumen.
 8. The method of claim 7 wherein thesubstance administered is a medicament selected from the groupconsisting of tetrachloroethylene, nicotine sulfate, bacitracin, zincbacitracin, manganese bacitracin and bacitracin methylenedisalicylate.9. The method of claim 7 wherein the substance administered is amedicament selected from the group consisting of chloramphenicol,tylosin, erythromycin, penicillin, tetracycline, oxytetracycline andchlortetracycline.
 10. The method of claim 7 wherein the substanceadministered is a member of the group consisting of the amino acidslysine, methionine, cystine, cysteine, tryptophan, arginine, threonine,and glycine and digestible peptides, polypeptides, and proteinscontaining the same.
 11. The method of claim 7 wherein the compound isadministered by drenching with an aqueous solution containing from about0.005 to about 2 percent of the compound, and wherein the substance isorally administered within about two minutes following theadministration of the drench.
 12. A method which comprises orallyadministering to a ruminant animal a finely divided solid, ingestiblecomposition comprising from about 0.005 to about 2 percent by weight ofa compound selected from the group consisting of guanidine,1-aminoguanidine, 1,3-diaminoguanidine and the pharmaceuticallyacceptable salts thereof, and a substance selected from the groupconsisting of dextrose, sucrose, lactose, maltose, corn syrup solids,hydrolyzed cereal solids, dry milk solids, cracked or milled grain,dried molasses, dried sorghum, soybean meal, cottonseed meal, peanutmeal, fish meal, lysine, methionine, cystine, cysteine, tryptophan,arginine, glycine, peptides and polypeptides containing lysine,cysteine, cystine, tryptophan, arginine, glycine, or methionine, casein,soya bean protein, vitamin A, vitamin D, vitamin E, and vitamin K; thecomposition being administered in an amount sufficient to provide fromabout 0.5 to about 1,000 milligrams of said compound per pound of animalbody weight, whereby said substance is shunted to the omasum-abomasum,substantially bypassing the reticulo-rumen.
 13. The method of claim 12wherein the compound is guanidine hydrochloride.
 14. The method of claim12 wherein the composition is administered in an amount sufficient toprovide from about 0.5 to about 25 milligrams of compound per pound ofanimal body weight.